BACE1 Deficiency Causes Altered Neuronal Activity and Neurodegeneration

Hu, X.; Zhou, X.; He, W.; Yang, J.; Xiong, W.; Wong, P.; Wilson, C. G.; Yan, R.

doi:10.1523/jneurosci.1334-10.2010

Cited by 164Alzheimer's disease research and treatmentsEpilepsy research and treatmentNeuroscience and Neuropharmacology Research

BACE1 Deficiency Causes Altered Neuronal Activity and Neurodegeneration

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Hu, X., Zhou, X., He, W., Yang, J., Xiong, W., Wong, P., Wilson, C. G., Yan, R.·2010·Journal of Neuroscience

DOI 10.1523/jneurosci.1334-10.2010PMC PMC2902368

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Abstract

BACE1 is required for the release of beta-amyloid (Abeta) in vivo, and inhibition of BACE1 activity is targeted for reducing Abeta generation in Alzheimer's patients. To further our understanding of the safe use of BACE1 inhibitors in human patients, we aimed to study the physiological functions of BACE1 by characterizing BACE1-null mice. Here, we report the finding of spontaneous behavioral seizures in BACE1-null mice. Electroencephalographic recordings revealed abnormal spike-wave discharges in BACE1-null mice, and kainic acid-induced seizures also occurred more frequently in BACE1-null mice compared with their wild-type littermates. Biochemical and morphological studies showed that axonal and surface levels of Na(v)1.2 were significantly elevated in BACE1-null mice, consistent with the increased fast sodium channel current recorded from BACE1-null hippocampal neurons. Patch-clamp recording also showed altered intrinsic firing properties of isolated BACE1-null hippocampal neurons. Furthermore, population spikes were significantly increased in BACE1-null brain slices, indicating hyperexcitability of BACE1-null neurons. Together, our results suggest that increased sodium channel activity contributes to the epileptic behaviors observed in BACE1-null mice. The knowledge from this study is crucial for the development of BACE1 inhibitors for Alzheimer's therapy and to the applicative study of epilepsy.

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BACE1 KO mice exhibit a variety of neurological defects.
“In addition, BACE1 KO mice exhibit a variety of neurological defects [641–643]”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [643]

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BACE1-/- mice exhibit seizure activity that does not correlate with sodium channel level or axonal localization
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Reduced Sodium Channel Nav1.1 Levels in BACE1-null Mice*
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Loss of Bace2 in zebrafish affects melanocyte migration and is distinct from Bace1 knock out phenotypes
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APP Knockout Mice Experience Acute Mortality as the Result of Ischemia
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miR‐15b mediates oxaliplatin‐induced chronic neuropathic pain through BACE1 down‐regulation
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BACE1 and presenilin/γ‐secretase regulate proteolytic processing of KCNE1 and 2, auxiliary subunits of voltage‐gated potassium channels
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Retinal Toxicity Induced by a Novel β-secretase Inhibitor in the Sprague-Dawley Rat
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β-Secretase BACE1 Regulates Hippocampal and Reconstituted M-Currents in a β-Subunit-Like Fashion
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SPON1 Can Reduce Amyloid Beta and Reverse Cognitive Impairment and Memory Dysfunction in Alzheimer’s Disease Mouse Model
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Implications for BACE1 Inhibitor Clinical Trials: Adult Conditional BACE1 Knockout Mice Exhibit Axonal Organization Defects in the Hippocampus
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β-Secretase Cleavage of the Fly Amyloid Precursor Protein Is Required for Glial Survival
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Alzheimer’s disease and epilepsy: An increasingly recognized comorbidity
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BACE1 elevation is associated with aberrant limbic axonal sprouting in epileptic CD1 mice
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Alzheimer disease: Amyloid peptide controversies and challenges of anti-Aβ immunotherapy
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The Swedish APP mutation alters the effect of genetically reduced BACE1 expression on the APP processing
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BACE1-Dependent Neuregulin-1 Signaling: An Implication for Schizophrenia
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BACE1 inhibitor drugs for the treatment of Alzheimer's disease: Lessons learned, challenges to overcome, and future prospects†
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Alzheimer's secretases regulate voltage-gated sodium channels
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β-Site APP-cleaving enzyme 1 (BACE1) cleaves cerebellar Na+ channel β4-subunit and promotes Purkinje cell firing by slowing the decay of resurgent Na+ current
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MicroRNA-9 induces defective trafficking of Nav1.1 and Nav1.2 by targeting Navβ2 protein coding region in rat with chronic brain hypoperfusion
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Amyloid Beta Hypothesis in Alzheimer's Disease: Major Culprits and Recent Therapeutic Strategies
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Prospects of β-Secretase Inhibitors for the Treatment of Alzheimer’s Disease
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Sodium channel β1 subunits participate in regulated intramembrane proteolysis-excitation coupling
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BACE1 modulates gating of KCNQ1 (Kv7.1) and cardiac delayed rectifier KCNQ1/KCNE1 (IKs)
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Highly Selective and Potent Human β‐Secretase 2 (BACE2) Inhibitors against Type 2 Diabetes: Design, Synthesis, X‐ray Structure and Structure–Activity Relationship Studies
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Opposite Roles of δ- and μ-Opioid Receptors in BACE1 Regulation and Alzheimer’s Injury
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Diverse impact of acute and long-term extracellular proteolytic activity on plasticity of neuronal excitability
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Combining an amyloid‐beta (Aβ) cleaving enzyme inhibitor with a γ‐secretase modulator results in an additive reduction of Aβ production
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BACE Inhibitor Clinical Trials for Alzheimer’s Disease
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BACE1 Is Necessary for Experience-Dependent Homeostatic Synaptic Plasticity in Visual Cortex
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BACE1-/- mice exhibit seizure activity that does not correlate with sodium channel level or axonal localization
Hitt, B. D., Jaramillo, T. C., Chetkovich, D. M., & Vassar, R. (2010) · Molecular Neurodegeneration · doi:10.1186/1750-1326-5-31 · Cited by 99 · see citing works
β-Secretase BACE1 Regulates Hippocampal and Reconstituted M-Currents in a β-Subunit-Like Fashion
Hessler, S., Zheng, F., Hartmann, S., Rittger, A., Lehnert, S., Völkel, M., Nissen, M., Edelmann, E., Säftig, P., Schwake, M., et al. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.3127-14.2015 · Cited by 38 · see citing works
β-Site APP-cleaving enzyme 1 (BACE1) cleaves cerebellar Na+ channel β4-subunit and promotes Purkinje cell firing by slowing the decay of resurgent Na+ current
Huth, T., Rittger, A., Säftig, P., & Alzheimer, C. (2011) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-010-0913-2 · Cited by 27 · see citing works
beta-Secretase BACE1 Regulates Hippocampal and Reconstituted M-Currents in a beta-Subunit-Like Fashion
Hessler, S., Zheng, F., Hartmann, S., Rittger, A., Lehnert, S., Voelkel, M., Nissen, M., Edelmann, E., Säftig, P., Schwake, M., et al. (2015) · PUB – Publications at Bielefeld University (Bielefeld University)
Bace1 Deletion in the Adult Reverses Epileptiform Activity and Sleep–wake Disturbances in AD Mice
Yao, A. Y., Halloran, P. J., Ge, Y., Singh, N., Zhou, J., Galske, J., He, W., Yan, R., & Hu, X. (2023) · Journal of Neuroscience · doi:10.1523/jneurosci.2124-22.2023 · Cited by 21 · see citing works
Self-citation

Authors: Hu, X., Zhou, X., He, W., Yang, J., Xiong, W., Wong, P., Wilson, C. G., & Yan, R.
Affiliations: Cleveland Clinic (US)
Augusta University (US)
Johns Hopkins University (US)
ORCID: Hu, X.
Xiong, W.
Wong, P.
Wilson, C. G.
Yan, R.
Venue: Journal of Neuroscience
Publisher: Society for Neuroscience
Published: 2010-06-30
Volume: 30
Issue: 26
Pages: 8819-8829
ISSN: 0270-6474 (ISSN-L)
1529-2401
DOI: 10.1523/jneurosci.1334-10.2010
PMC: PMC2902368
OpenAlex: W2017917068
Cited by: 162
References: 55
Citations by year: 2026: 4 · 2025: 10 · 2024: 7 · 2023: 5 · 2022: 8 · 2021: 4 · 2020: 9 · 2019: 7 · 2018: 8 · 2017: 5 · 2016: 13 · 2015: 11 · 2014: 19 · 2013: 16 · 2012: 16
FWCI: 11.47
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Neuroscience (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Alzheimer's Association (AG025493)
American Health Assistance Foundation (AG025493)
Wilson Foundation
Ralph C. Wilson Foundation (AG025493)
National Institutes of Health (AG025493)
National Institute on Aging (R01AG025493, RF1AG025493, AG025493)
National Heart, Lung, and Blood Institute (R01HL081622, HL081622)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: BACE1, amyloid-beta, Alzheimer's disease, BACE1 inhibitors, spontaneous seizures, spike-wave discharges, kainic acid-induced seizures, fast sodium current, hippocampal neurons, neuronal hyperexcitability, epilepsy, neurodegeneration
MeSH terms: Action Potentials, Aging, Animals, Axons, Brain, Cell Membrane, Hippocampus, Kainic Acid, Membrane Potentials, Nerve Degeneration, Neurons, Phenotype, Seizures, Sodium Channels, Aspartic Acid Endopeptidases, Mice, Knockout, Mice, Amyloid Precursor Protein Secretases, In Vitro Techniques

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BACE1 Deficiency Causes Altered Neuronal Activity and Neurodegeneration

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